Genetic counseling: Medium-chain acyl-coenzyme A dehydrogenase Deficiency
Medium-chain acyl-coenzyme A dehydrogenase Deficiency Overview *Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is an enzyme involved in mitochondrial fatty acid b-oxidation (FAO). Fatty acid oxidation provides energy for peripheral tissues when glycogen is depleted through hepatic ketogenesis. A defect in the MCAD enzyme causes accumulation of medium-chain fatty acids, metabolized to glycine- and carnitine-esters and dicarboxylic acids, and hypoketonia. Genetics *MCAD deficiency is caused by a mutation in the ACADM gene *Chromosomal locus 1p31 *31 known disease causing mutations *1 common mutation, K304E, accounts for 76% of alleles Incidence *Common in Caucasians, especially with Northern European ancestry *Disease incidence 1:4,900 to 1:17,000 *Carrier frequency 1:40 to 1:100 *Less common among Hispanics *Rare in African-American, and Native-American populations Diagnosis *Metabolic testing *Symptomatic individuals should have plasma acylcarnitines, plasma fatty acids, urine organic acids, and urine acylclycines analyzed and interpreted. *Enzymatic testing *MCAD enzyme activity should be measured in fibroblasts or other tissues to confirm diagnosis *Molecular testing *Molecular genetic testing by mutation analysis (for K204E) or sequence analysis of the ACADM gene can confirm diagnosis *Newborn screening *MCAD is part of the newborn screening panel in 9 states (IA, ME, MA, NC, OH, SC, SD, WI, WY). *Prenatal testing *Enzymatic or molecular testing can be performed prenatally; however, there is limited benefit to prenatal vs. newborn testing. *Carrier testing *Only molecular testing can determine carrier status. Clinical Features *Typical presentation includes hypoketotic hypoglycemia, vomiting, lethargy, seizures, and coma precipitated by prolonged fasting or common illness. *Hepatomegaly and acute liver disease may also be present. *Sudden, unexplained death may be first symptom (18%). Natural History *Typically normal at birth following uneventful pregnancy *Most present with symptoms between 3 and 24 months in response to prolonged fasting or infection *Initial presentation in adulthood also possible *Affected individuals may lose developmental milestones or acquire aphasia or ADD as a result of acute metabolic event *Individuals identified as newborns typically develop normally under treatment Inheritance *MCAD deficiency is an autosomal recessive disorder. Testing *Enzymatic and Molecular testing can confirm diagnosis. *Both mutation and sequence analysis are available on a clinical basis. Management & Treatment *MCAD is a highly treatable condition- good prognosis when managed *Avoidance of fasting is key- *Infants should be fed frequently *Toddlers should be given 2 g/kg uncooked cornstarch before bed *Low-fat diet and carnitine supplementation may be beneficial Differential Diagnosis *Other disorders of acyl-CoA dehydrogenase (ACAD) gene family *Other disorders of fatty acid b-oxidation Psychosocial Issues *Parental guilt over allowing too long of time between feedings which triggered onset of symptoms *Parental guilt over passing gene to child *When presenting symptom is sudden death, loss of seemingly healthy child can be devastating *Parent or sibling may be identified as a homozygote during carrier testing *Family planning- risk for future offspring/siblings of affected individual Patient Resources *FOD (Fatty Oxidation Disorder) Family Support Group :805 Montrose Drive :Greensboro, NC 27410 :Phone: (336) 547-8682 :Email: deb@fodsupport.org :Web: www.fodsupport.org *Organic Acidemia Association :13210 35th Avenue North :Plymouth, MN 55441 :Phone; (763) 556-1797 :Email: OAANews@aol.com :Web: www.oaanews.org *United Mitochondrial Disease Foundation :8085 Saltsburg Road, Suite 201 :Pittsburgh, PA 15239 :Phone: (412) 793-8077 :Email: info@umdf.org :Web: www.umdf.org Notes The informaiton in this outline was last updated in Feb 2003. This material has been imported fom the wikibook "Genetic counseling"[ http://en.wikibooks.org/wiki/Genetic_counseling] under the GNU Free Documentation License.